WASP levels in platelets and lymphocytes of Wiskott-Aldrich syndrome patients correlate with cell dysfunction

Wiskott-Aldrich syndrome, an inherited blood cell disorder due to mutations of the X-chromosome gene WASP (Wiskott-Aldrich syndrome protein), was char acterized originally by thrombocytopenia, immunodeficiency, and eczema. Whe reas platelet dysfunction is severe and consistent, immune defects are clin ically variable, ranging from negligible to life threatening, To understand this heterogeneity, we quantified WASP in PBMC and platelets, and also in neutrophils, of patients with diverse mutations. A surprisingly complex pat tern of WASP expression found for lymphoid cells formed the basis for divid ing the patient mutations into four groups, Group A have low WASP levels in PBMC and higher levels in EBV cell lines, as wed as near normal WASP RNA l evels (7 patients, most with mild disease), suggesting that group A WASP mo lecules are hypersusceptible to proteolysis, Group B have low WASP levels i n PBMC and EBV cells and similar low RNA levels (2 patients, moderate disea se). Group C have discordant expression: WASP-positive peripheral T cells a nd WASP-negative peripheral B cells and EBV cell lines (9 patients, variabl e disease severity). Noteworthy among group C kindred are several instances of B cell lymphomas, In group D, PBMC and EBV cell lines are WASP negative (7 patients, severe disease), In contrast to the complex lymphoid cell exp ression patterns, all patient platelets examined were WASP negative (18 div erse patients). WASP absence in platelets provides an apparent molecular ex planation for the universally severe platelet dysfunction in this disease, and the cumulative lymphoid cell findings suggest that WASP levels play a s ubstantial role in determining immune outcome.